There is a critical need to identify novel mechanisms of diabetic kidney disease (DKD) that will provide targets for new interventions. Chronic inflammation is one plausible mechanism. Using untargeted high-throughput aptamer proteomics, our recently published study has shed new light on specific, key inflammatory drivers of DKD. This was a large prospective three-cohort study that identified a novel and extremely robust circulating signature (KRIS) associated with risk of ESRD in diabetes. Our pilot study points to the data-driven connection between circulating KRIS and urinary profiles of the Complement pathway. Our hypothesis is that the Complement involvement in the kidney is a downstream effect of the systemic inflammatory processes mediating an increased DKD risk. The overarching goal of this proposal is to provide a high-resolution view of the involvement of the Complement proteome in progressive diabetic kidney disease. Aim 1 will comprehensively evaluate the etiological role of the urinary Complement proteome in progressive DKD leading to ESRD. This evaluation will leverage a prospective two-cohort population of Joslin Kidney Study (JKS) participants with an overt DKD at baseline followed for 10 years (primary outcome ? incident ESRD). Measurements will utilize an aptamer proteomic technology (SOMAscan). Aim 2 will extend generalizability of the urinary Complement proteome to earlier DKD stages. The proposed study will be conducted in participants of the Preventing Early Renal Loss (PERL) clinical trial with predominantly normal renal function at baseline followed for 3 years (primary outcome - renal slope). Aim 3 proposes to gain direct insight into the intra-renal Complement proteome by targeted and untargeted protein studies in diabetic kidney tissue (Susztaklab Biobank). This project focuses on a significant public health problem, leverages the progressiveness of the disease, employs an innovative proteomic technology and stems from strong preliminary data. Advances in this project will pinpoint missing key components of DKD etiology, thereby accelerating drug development strategies for patients with diabetes.